Production of toxic organo phosphorus compounds

ABSTRACT

1. A method of producing a compound of the formula   which comprises cyclizing in an alkaline aqueous solution a beta-chloroethylamine of the formula   to thereby form a solution containing the ethyleneimmonium ion   and reacting said ionized solution with an alkali metal salt of the formula   R and R1 in the above formulas being selected from the class consisting of alkyl and alkoxy groups, R2 and R3 being alkyl groups containing more than one carbon atom, and M being selected from the class consisting of sodium and potassium.

United States Patent [191 Epstein et al.

[4 1 Sept. 2, 1975 1 PRODUCTION OF TOXIC ORGANO PHOSPHORUS COMPOUNDS [75] Inventors: Joseph Epstein, Baltimore, Md.;

Kenneth E. Levy, Los Angeles,

Calif.; Harry 0. Michel, Towson, Md.

[73] Assignee: The United States of America as represented by the Secretary of the Army, Washington, DC.

22 Filed: Apr. 22, 1958 21 App]. No.: 730,758

[52] US. Cl 260/978; 260/239 C; 260/979;

260/999; 424/21 1 51 im. cl. C07F 9/165 [58] Field of Search 260/461.309, 461.310,

[56] References Cited UNITED STATES PATENTS 2,736.726 2/1956 Gaetzi ct al 260/979 X 2,767,194 10/1956 Francher 424/200 X FOREIGN PATENTS OR APPLICATIONS 783,281 9/1957 United Kingdom Primary E.\'aminer-Leland A. Sebastian Attorney, Agent, or Firm-Nathan Edelberg; Robert P. Gibson; Kenneth P. Van Wyck EXEMPLARY CLAIM l. A method of producing a compound of the formula which comprises cyclizing in an alkaline aqueous solution a beta-chloroethylamine of the formula to thereby form a solution containing the ethyleneim monium ion and reacting said ionized solution with an alkali metal salt of the formula bon atom, and M being selected from the class consisting of sodium and potassium.

11 Claims, No Drawings l PRODUCTION OF TOXIC ORGANO PHQSPHORUS COMPOUNDS V This invention described herein may be manufactured and used by or for Government of the United States of America for governmental purposes without the payment to us of any royalty thereon.

This invention relates to the production of toxic organic compounds of the formula wherein R and R are alkyl or alkoxy groups, preferably methyl, methoxy, ethyl, ethoxy, isopropyl, or isopropoxy, and R and R are alkyl groups containing more than one carbon atom, preferably ethyl or isopropyl. (If

R and/or R are methyl the process is unsuccessful).

The method comprises cyclizing a betachloroethyl dialkyl amine in a strongly basic aqueous solution, thereby giving a dialkylethyleneimmonium ion, and reacting the ionized solution with the sodium or potassium salt of the proper phosphorus-containing acid.

These compounds are useful as chemical warfare toxic agents. They have low volatilities and are usable in weapons such as bombs, shells, aerosol generators, etc., which are adapted to disseminate relatively nonvolatile agents.

The process may also be used to prepare toxic compounds in situ in bodies of water, such as ponds, lakes, streams, etc. The reaction will take place in extremely dilute solutions, although the rate of reaction is relatively slow under those conditions. The bimolecular reaction rate constant for the reaction between the ethyl ene immonium ion and the phosphorothiolate ion has been found to be about 2.5 liters per mole per hour, and that between the ethyleneimmonium ion and the phosphonothiolate ion about 4 liters per mole per hour. Thus the cyclized amine solution and the phosphoro, phosphono, or phosphinothiolate solutions, which are non-toxic, may be added to a body of water and there allowed to react to produce the toxic compound.

Alternatively, the reactants may be mixed in a container shortly before use and allowed to react. The reaction mixture may then be added to the body of water.

This procedure may be used for pesticidal purposes.

One embodiement of the method comprises the following steps:

a. Adding an aqueous solution of the hydrochloride of a beta-chloroethyl dialkyl amine,

to an aqueous solution of an alkali metal dialkyl phosphorothiolate an alkali metal alkyl alkylphosphonothiolate or an alkali metal phosphinothiolate wherein M is sodium or potassium and R, R, R and R are alkyl groups, under strongly alkaline conditions.

b. allowing the mixture to stand until the reaction represented by the equation has taken place, and

c. extracting the organic product from the aqueous alkali metal chloride solution with a water immiscible l N+ H I Ril and the chloride ion. Through the measurement of chloride ion production, it has been established that a complete ionization of the amine molecule takes place in less than 10 minutes at pH 10. i

The immonium ion then apparently adds directly to the phosphorothiolate, phosphonothiolate, or phos phinothiolate ion to give the final product.

Several other variations of the general method set out above are given in the discussion which follows.

The following Examples illustrate our process.

EXAMPLE 1 0,0-Diethyl S-Diethylaminoethyl Phosphorothiolate To I00 ml. of water containing 6.2 g of the potassium salt of diethylphosphorothiolate (0.03 moles), adjusted to pH l0 by addition of concentrated sodium hydroxcontaining 1 g (0.02 moles) of the hydrochloride. The solutions weremixed well until the solution showed a maximum and constant anticholinesterase activity (approximately 3 hours at room temperature). The pH was adjusted to l0.5 and the mixture extracted with five 50 ml. portions of distilled benzene (until the aqueous phase showed negligible anticholinesterase activity) and the extract was dried over anhydrous sodium sulfate. The benzene solution was placed in a shallow evaporating dish and the benzene allowed to evaporate to constant volume. The oil in the evaporat ing dish was washed into a distilling apparatus with a small quantity of dried ethyl ether. The ether solution was subjected to fractional distillation at reduced pressure. Thecompound boiled at 9698/ca 0.5 mm Hg. It had an anticholinesterase activity of 93 percent of the most potent sample of 0,0-Diethyl S- Diethylaminoethyl Phosphorothiolate yet tested. Based on comparison of the anticholinesterase activity of the aqueous solution with that of the pure compound, the yield in solution was about 58 percent. The isolated product was obtained in a yield of about 40 percent, based on the amine salt.

Another experiment carried out in the same manner, but using a molar ratio of potassium salt to amine salt of 4.] gave a yield (in solution) of 87 percent.

We have found that side reactions can be minimized by beginning the reaction at a higher pH, then, after the initial cyclization period, adding acid to lower the pH. Example 2 illustrates this practice and also shows the production of the phosphonothiolate type compounds.

EXAMPLE 2 O-Ethyl S-Diethylaminoethyl Ethylphosphonothiolate To 50 ml. of a 0.4 M NaOH solution (0.02 moles) was added 100 ml. of an aqueous solution containing 9.17 g of potassium ethylphosphonothiolate of 84 percent purity (0.04 moles). Then 200 ml. of an aqueous solution containing 3.44 g (0.02 moles) of betachloroethyl diethylamine ,hydrochloride was added. The solutions were mixed and allowed to stand for 5 minutes. The pH of the solution was between 10.0 and 10.5. After 5 minutes, 50 ml. of 0.04 M acetic acid was added. The pH dropped to 5.15. The solutions were mixed well and at various time intervals aliquots were extracted and tested for anticholinesterase activity until the activity was constant. The pH had increased to approximately 8.8 at the time of constant activity.

The solution was then brought to pH 10.5 and extracted with diethyl ether until the aqueous phase had negligible anticholinesterase activity. The ether extract was dried over anhydrous sodium sulfate and distilled. The overall yield after distillation was 70 percent. The yield in solution was 75 percent based on anticholinesterase activity.

The recovered sample was compared with a highly purified sample of O-ethyl S-diethylaminoethyl ethylphosphonothiolate prepared by a different method. The sample produced in this Example had 92 percent of the anticholinesterase activity of the purified sample.

Still another variation that has yielded excellent results involves adding the amine hydrochloride to sodium hydroxide, allowing cyclization to take place,

adding, an .acid. to lower the pH, and thereafter adding the phosphorothiolate salt. V i

Example 3 illustrates this variation.

EXAMPLE 3 0,0-Diethyl S-Diethylaminoethyl Phosphorothiolat e A 0.048 molar aqueous solution of betac'hloroethyl diethylamine hydrochloride was made alkaline by addition of two equivalents of NaOH. After 5 minutes an exesss of acetic acid was added, lowering the pH to 4.6 A 0.106 molar solution of potassium diethylphosphorothiolate was then added. A yield, in solution, of virtually percent was obtained. About 45 hours was required for the reaction to go to completion.

EXAMPLE 4 O-Ethyl S-Diethylaminoethyl Methylphosphonothiolate Potassium ethyl methylphosphonothiolate is added to an aqueous solution of sodium hydroxide and the solution adjusted to pH 10. An aqueous solution of beta-chloroethyldiethylamine hydrochloride at pH 10 is then added and the reaction mixture treated in the same manner as in Example 2.

EXAMPLE 5 0,0Diisopropyl S-Diethylaminoethyl Phosphorothiolate The potassium salt of diisopropyl phosphorothiolate is added to an aqueous solution of sodium hydroxide and the pH adjusted to 10. An aqueous solution of beta-chloroethyldiethylamine hydrochloride at pH 10 is added and the mixture treated in the same manner as in Example 2.

EXAMPLE -6 O-lsopropyl-S-Diethylaminoethyl lsopropylphosphonothiolate Sodium isopropyl isopropylphosphonate is dissolved in water and the pH adjusted to 10 by addition of concentrated sodium hydroxide. An aqueous solution of beta-chloroethyldiethylamine hydrochloride at pH 10 is added and the mixture is then treated in the same manner as in Example 2.

EXAMPLE 7 S-Diethylaminoethyl Ethylethylphosphinothiolate Potassium ethylethylphosphinothiolate is dissolved in water and the pH adjusted to 10 by addition of concentrated sodium hydroxide. An aqueous solution of beta-chloroethyldiethylamine at pH 10 is then added and the mixture treated in the same manner as in Example 2.

EXAMPLE 8 O-Isopropyl-S- Diisopropylaminocthyl Methylphosphonothiolate Potassium isopropyl methylphosphonothiolate is dissolved in water and the pH of the solution is ajusted to 10 by addition of concentrated sodium hydroxide. An aqueous solution of beta-chloroethyl diisopropylaminc at pH 10 is added. The mixture is then treated in the same manner as Example 2.

EXAMPLE 9 Preparation of a Toxic Compound in Situ Fifteen pounds of betachloroethyl diethylamine hydrochloride is dissolved in 100 gallons of water and the solution is brought to pHlO by addition of sodium hydroxide. After standing for at least 10 minutes, it is added to a pond containing 100,000 gallons of water. Fifteen pounds of sodium ethyl methylphosphonothio late is then added in aqueous solution. In 25 hours the pond contains 0.2 parts per million of O-ethyl S- diethylaminoethyl methylphosphonothiolate, which concentration is extremely toxic to small fish species and to small mammals. such as rats. The concentration continues to increase with time. When the desired kill has been accomplished, the pond is decontaminated by chlorination.

The method of this invention is particularly advantageous in the following respects:

a. The salts used are soluble in the solvent (water) so that the reaction takes place in a homogenous phase.

b. The reaction proceeds at room temperature without need for either heating or cooling.

c. The by-product, sodium chloride, is soluble in the solvent. The main product is likewise partially water soluble but is readily removed by extraction with waterimmisicible solvents. lt is therefore unnecessary to employ filtration, which is particularly undesirable in handling these highly toxic materials. Extraction and distillation can be carried out continuously in completely enclosed system.

d. A product of high purity is obtained with a minimum amount of purification.

c. It is suitable for the preparation of toxic compounds in situ in aqueous solution.

We claim:

I. A method of producing a compound of the formula which comprises cyclizing in an alkaline aqueous solution a bcta-chloroethylamine of the formula to thereby form a solution containing the ethyleneimmonium ion and reacting said ionized solution with an alkali metal salt of the formula R and R in the above formulas being selected from the class consisting of alkyl and alkoxy groups, R and R being alkyl groups containing more than one carbon atom. and M being selected from the class consisting of sodium and potassium.

2. A method as defined in claim 1 comprising dissolving the said salt and the hydrochloride of said amine in a strongly alkaline aqueous solution, allowing said solution to stand until the cyclization has taken place, then acidifying said solution and allowing it to stand until it attains a substantially maximum and constant anticholinesterase activity.

3. A method as defined in claim 1 comprising adding sufficient alkaline hydroxide to an aqueous solution of the hydrochloride of said amine to give a pH of about 10, allowing said solution to stand until cyclization has taken place, acidifying said solution, adding said salt to said solution and allowing it to stand until it attains a substantially maximum and constant anticholinesterase activity.

4. A method as defined in claim 1 comprising adding an aqueous solution of the hydrochloride of said amine to a strongly alkaline aqueous solution of said saltand allowing said mixture to stand until it attains a substantially maximum and constant anticholinesterase activity.

5. A method of producing a compound of the formula which comprises adding a beta-chloroethyl dialkylamine hydrochloride of the formula to a strongly alkaline aqueous solution of a compound of the formula which comprises adding an aqueous solution of a beta-chloroethyldialkylamine hydrochloride of the formula to a strongly alkaline solution of a compound of the for mula R and R in the above formulas being alkyl groups R and R being alkyl groups containing more than one carbon atom and M being selected from the class consisting of sodium and potassium, and allowing the mixture to stand until reaction has taken place.

7. A method of producing 0,0-diethyl S- diethylaminoethyl phosphorothiolate which comprises adding an aqueous solution of beta chloroethyl diethylamine hydrochloride to a strongly alkaline aqueous solutionnof sodium 0,0-diethyl phosphorothiolate and allowing the mixture to stand until reaction has taken place.

8. A method of producing an O-alkyl S- dialkylaminoethyl alkylphosphonothiolate which comprises adding a beta chloroethyl dialkylamine hydrochloride to a strongly alkaline solution of a compound of the formula wherein R and R are alkyl groups and M is selected from the class consisting of sodium and potassium, and allowing the mixture to stand until reaction has taken place.

9. A method of producing O-ethyl S- diethylaminoethyl ethylphosphonothiolate which comprises adding beta ehloroethyl diethylamine hydrochloride to a strongly alkaline aqueous solution of sodium O-ethylphosphonothiolate and allowing the mixture to stand until reaction has taken place.

10. A method of preparing a toxic compound in situ in a body of water comprising cyclizing in a strongly basic aqueous solution a beta-chloroethyl dialkyl amine of the formula to thereby form a solution containing the ethylene immonium ion adding said ionized solution to said body of water, and adding to said body of water an alkali metal salt of the formula I l S cHz- CH2- 3 1 V K which comprises cyclizing in a strongly alkaline aqueous solution a beta-chloroethylene of the formula R -N-CH-CH-CI 2 2 R3 to thereby form a solution containing the ethylene immonium ion 2 R CH2 l Chi and reacting said ionized solution with an alkali metal salt of the formula R-P-SM R and R in the above formulas being selected from the group consisting of methyl. methoxy. ethyl. ethoxy. isopropyl, and isopropoxy and R and R are selected from the group consisting of ethyl and isopropyl and M being selected from the group consisting of sodium and potassium. 

1. A METHOD OF PRODUCING A COMPOUND OF THE FORMULA
 2. A method as defined in claim 1 comprising dissolving the said salt and the hydrochloride of said amine in a strongly alkaline aqueous solution, allowing said solution to stand until the cyclizatIon has taken place, then acidifying said solution and allowing it to stand until it attains a substantially maximum and constant anticholinesterase activity.
 3. A method as defined in claim 1 comprising adding sufficient alkaline hydroxide to an aqueous solution of the hydrochloride of said amine to give a pH of about 10, allowing said solution to stand until cyclization has taken place, acidifying said solution, adding said salt to said solution and allowing it to stand until it attains a substantially maximum and constant anticholinesterase activity.
 4. A method as defined in claim 1 comprising adding an aqueous solution of the hydrochloride of said amine to a strongly alkaline aqueous solution of said salt and allowing said mixture to stand until it attains a substantially maximum and constant anticholinesterase activity.
 5. A method of producing a compound of the formula
 6. A method of making an O,O-dialkyl S-dialkylaminoethyl phosphorothiolate of the formula
 7. A method of producing O,O-diethyl S-diethylaminoethyl phosphorothiolate which comprises adding an aqueous solution of beta chloroethyl diethylamine hydrochloride to a strongly alkaline aqueous solution of sodium O,O-diethyl phosphorothiolate and allowing the mixture to stand until reaction has taken place.
 8. A method of producing an O-alkyl S-dialkylaminoethyl alkylphosphonothiolate which comprises adding a beta chloroethyl dialkylamine hydrochloride to a strongly alkaline solution of a compound of the formula
 9. A method of producing O-ethyl S-diethylaminoethyl ethylphosphonothiolate which comprises adding beta chloroethyl diethylamine hydrochloride to a strongly alkaline aqueous solution of sodium O-ethylphosphonothiolate and allowing the mixture to stand until reaction has taken place.
 10. A method of preparing a toxic compound in situ in a body of water comprising cyclizing in a strongly basic aqueous solution a beta-chloroethyl dialkyl amine of the formula
 11. A method of producing a compound of the formula 